1. Field of the Invention
The present invention relates to stable pharmaceutical solution formulations to be used with pressurized metered dose inhalers (MDIs) suitable for aerosol administration. In particular, the present invention relates to solutions to be used with pressurized metered dose inhalers (MDIs), which are suitable for aerosol administration, which contain a β2-agonist, and which are stable at room temperature for a pharmaceutically acceptable shelf-life.
2. Discussion of the Background
Pressurized metered dose inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation.
Drugs commonly delivered by inhalation include bronchodilators such as β2-agonists and anticholinergics, corticosteroids, anti-leukotrienes, anti-allergics, and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
MDIs use a propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol. Formulations for aerosol administration via MDIs can be solutions or suspensions. Solution formulations offer the advantage of being homogeneous with the active ingredient and excipients completely dissolved in the propellant vehicle or its mixture with suitable co-solvents such as ethanol. Solution formulations also obviate physical stability problems associated with suspension formulations so assuring more consistent uniform dosage administration.
For many years the preferred propellants used in aerosols for pharmaceutical use have been a group of chlorofluorocarbons which are commonly called Freons or CFCs, such as CCl3F (Freon 11 or CFC-11), CCl2F2 (Freon 12 or CFC-12), and CClF2—CClF2 (Freon 114 or CFC-114).
Recently, the chlorofluorocarbon (CFC) propellants such as Freon 11 and Freon 12 have been implicated in the destruction of the ozone layer and their production is being phased out.
Hydrofluoroalkanes ((HFAs) known also as hydro-fluoro-carbons (HFCs)) contain no chlorine and are considered less destructive to ozone and these are proposed as substitutes for CFCs.
HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants and a number of medicinal aerosol formulations using such HFA propellant systems have been disclosed.
Due to the higher polarity of the HFA propellants, in particular of HFA 134a (dielectric constant D≧9.5), with respect to CFC vehicles (D≦2.3), HFA solution formulations may suffer to a greater extent from chemical stability problems with respect to the corresponding CFC formulations.
Preparation of stable HFA solution formulations is even more critical when bronchodilator β2-agonists belonging to the class of the phenylalkylamino derivatives are concerned. Said drugs, like formoterol, 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone hydrochloride (hereinafter referred as TA 2005), salbutamol (albuterol) and others, may suffer from inherent chemical stability problems due to their susceptibility to oxidative conditions. Moreover, in view of the presence of some functional groups like formamide, a higher polarity of the vehicle may accelerate the rate of solvolysis reactions.
As for formoterol, the currently marketed CFC solution formulation (Foradil®) exhibits a limited shelf life, i.e., 12 months at refrigerator temperature, 4±2° C., and only 3 months at room temperature.
As for salbutamol, no formulation as an HFA solution for aerosol administration is currently on the market.
In the case of TA 2005, no formulation at all is currently available for aerosol administration.
In consideration of the problems outlined above, it would be highly advantageous to provide formulations in the form of HFA solutions to be administered by MDIs which afford pharmaceutical doses of β2-agonists characterized by having an adequate shelf-life.